Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries

Research output: Contribution to journalJournal articleResearchpeer-review

  • Michael E Talkowski
  • Jill A Rosenfeld
  • Ian Blumenthal
  • Vamsee Pillalamarri
  • Colby Chiang
  • Adrian Heilbut
  • Carl Ernst
  • Carrie Hanscom
  • Elizabeth Rossin
  • Amelia M Lindgren
  • Shahrin Pereira
  • Douglas Ruderfer
  • Andrew Kirby
  • Stephan Ripke
  • David J Harris
  • Ji-Hyun Lee
  • Kyungsoo Ha
  • Hyung-Goo Kim
  • Benjamin D Solomon
  • Andrea L Gropman
  • And 15 others
  • Diane Lucente
  • Katherine Sims
  • Toshiro K Ohsumi
  • Mark L Borowsky
  • Stephanie Loranger
  • Bradley Quade
  • Kasper Lage Hansen
  • Judith Miles
  • Bai-Lin Wu
  • Yiping Shen
  • Benjamin Neale
  • Lisa G Shaffer
  • Mark J Daly
  • Cynthia C Morton
  • James F Gusella

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.

Original languageEnglish
Issue number3
Pages (from-to)525-37
Number of pages13
Publication statusPublished - 27 Apr 2012

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