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<p>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&#xa0;(SVs), and DNA methylation. Using LRS pangenome controls, we efficiently filtered &gt;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&amp;Tag data from the developing cortex. In total, we identified three pathogenic variants in <i>TBL1XR1</i>, <i>MECP2</i>, and <i>SYNGAP1</i>, 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.</p>

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Using the linear references from the pangenome to discover missing autism variants

  • 期刊论文

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  • 发表日期：

    2026年1月23日

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  • 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 Hennick,
  • Druha Karunakaran,
  • Rafael A. Polo Prieto,
  • Rebecca Meyer-Schuman,
  • Fisher Cherry,
  • Davut Pehlivan,
  • Bernhard Suter,
  • Jonas A. Gustafson,
  • Danny E. Miller,
  • Derek Albracht,
  • Ivan A. Alexandrov,
  • Jamie 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,
  • Andrew Carroll,
  • Ann M. Mc Cartney,
  • Monika Cechova,
  • Pi-Chuan Chang,
  • Xian Chang,
  • Jitender Cheema,
  • Haoyu Cheng,
  • Claudio 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,
  • Evan E. Eichler,
  • Jordan M. Eizenga,
  • Parsa Eskandar,
  • Eddie Ferro,
  • Anna-Sophie Fiston-Lavier,
  • Sarah M. Ford,
  • Willard W. Ford,
  • Giulio Formenti,
  • Adam Frankish,
  • Mallory A. Freeberg,
  • Qichen Fu,
  • Stephanie M. Fullerton,
  • Robert S. Fulton,
  • Yan Gao,
  • Obed A. 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 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,
  • Todd L. Hillaker,
  • S. Nakib Hossain,
  • Neng Huang,
  • Sarah E. Hunt,
  • Toby Hunt,
  • Alexander G. Ioannidis,
  • Nafiseh Jafarzadeh,
  • Nivesh Jain,
  • Erich D. Jarvis,
  • Maryam Jehangir,
  • Juan Jiang,
  • Edward A. Belter Jr,
  • Jonathan LoTempio Jr,
  • Eimear E. Kenny,
  • Juhyun Kim,
  • Bonhwang Koo,
  • Sergey Koren,
  • Milinn Kremitzki,
  • Charles H. Langley,
  • Ben Langmead,
  • Heather A. Lawson,
  • Daofeng Li,
  • Heng Li,
  • Wen-Wei Liao,
  • Tianjie Liu,
  • Glennis A. Logsdon,
  • Ryan Lorig-Roach,
  • Hailey Loucks,
  • Jane E. Loveland,
  • Jianguo Lu,
  • Shuangjia Lu,
  • Julian K. Lucas,
  • Juan F. Macias-Velasco,
  • Kateryna D. Makova,
  • Maximillian G. Marin,
  • Christopher Markovic,
  • Tobias Marschall,
  • Franco L. Marsico,
  • Fergal J. Martin,
  • Mira Mastoras,
  • Capucine Mayoud,
  • Brandy McNulty,
  • Jack A. Medico,
  • Julian M. Menendez,
  • Karen H. Miga,
  • Anna Minkina,
  • Matthew W. Mitchell,
  • Saswat K. Mohanty,
  • Younes Mokrab,
  • Jean Monlong,
  • Shabir Moosa,
  • Avelina Moreno-Ochando,
  • Shinichi Morishita,
  • Jonathan M. Mudge,
  • Njagi Mwaniki,
  • Nasna Nassir,
  • Chiara Natali,
  • Shloka Negi,
  • Lingbin Ni,
  • Adam M. Novak,
  • Pilar N. Ossorio,
  • Chie Owa,
  • Sadye Paez,
  • Benedict Paten,
  • Clelia Peano,
  • Adam M. Phillippy,
  • Brandon D. Pickett,
  • Laura Pignata,
  • Nadia Pisanti,
  • David Porubsky,
  • Pjotr Prins,
  • Anandi Radhakrishnan,
  • T. Rhyker Ranallo-Benavidez,
  • Brian J. Raney,
  • Mikko Rautiainen,
  • Alessandro Raveane,
  • Luyao Ren,
  • Arang Rhie,
  • Fedor Ryabov,
  • Samuel Sacco,
  • Farnaz Salehi,
  • Michael C. Schatz,
  • Laura B. Scheinfeldt,
  • Aarushi Sehgal,
  • William E. Seligmann,
  • Mahsa Shabani,
  • Kishwar Shafin,
  • Shadi Shahatit,
  • Ruhollah Shemirani,
  • Vikram S. Shivakumar,
  • Swati Sinha,
  • Jouni Sirén,
  • Linnéa Smeds,
  • Steven J. Solar,
  • Marco Sollitto,
  • Nicole Soranzo,
  • Andrew B. Stergachis,
  • Marie-Marthe Suner,
  • Yoshihiko Suzuki,
  • Arda Söylev,
  • Ahmad Abou Tayoun,
  • Jack A. S. Tierney,
  • Chad Tomlinson,
  • Francesca Floriana Tricomi,
  • Mohammed Uddin,
  • Matteo Tommaso Ungaro,
  • Rahul Varki,
  • Flavia Villani,
  • Ivo Violich,
  • Mitchell R. Vollger,
  • Brian P. Walenz,
  • Charles Wang,
  • Lisa E. Wang,
  • Ting Wang,
  • Aaron M. Wenger,
  • Conor V. Whelan,
  • Zilan Xin,
  • Zheng Xu,
  • Kai Ye,
  • DongAhn Yoo,
  • Wenjin Zhang,
  • Ying Zhou,
  • Xiaoyu Zhuo,
  • Giulia Zunino,
  • Hanna Berk-Rauch,
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  • Evan E. Eichler

摘要

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.