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

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. GropmanDiane Lucente, Katherine Sims, Toshiro K. Ohsumi, Mark L. Borowsky, Stephanie Loranger, Bradley Quade, Kasper Lage, Judith Miles, Bai Lin Wu, Yiping Shen, Benjamin Neale, Lisa G. Shaffer, Mark J. Daly, Cynthia C. Morton, James F. Gusella

Research output: Contribution to journalArticlepeer-review

425 Scopus citations


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 (US)
Pages (from-to)525-537
Number of pages13
Issue number3
StatePublished - Apr 27 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


Dive into the research topics of 'Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries'. Together they form a unique fingerprint.

Cite this