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Cell DOI:10.1016/j.cell.2012.03.028

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

Publication TypeJournal Article
Year of Publication2012
AuthorsTalkowski, ME, Rosenfeld, JA, Blumenthal, I, Pillalamarri, V, Chiang, C, Heilbut, A, Ernst, C, Hanscom, C, Rossin, E, Lindgren, AM, Pereira, S, Ruderfer, D, Kirby, A, Ripke, S, Harris, DJ, Lee, J-H, Ha, K, Kim, H-G, Solomon, BD, Gropman, AL, Lucente, D, Sims, K, Ohsumi, TK, Borowsky, ML, Loranger, S, Quade, B, Lage, K, Miles, J, Wu, B-L, Shen, Y, Neale, B, Shaffer, LG, Daly, MJ, Morton, CC, Gusella, JF
Date Published2012 Apr 27
KeywordsAutistic Disorder, Child, Child Development Disorders, Pervasive, Chromosome Aberrations, Chromosome Breakage, Chromosome Deletion, DNA Copy Number Variations, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Nervous System, Schizophrenia, Sequence Analysis, DNA, Signal Transduction

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.


Alternate JournalCell
PubMed ID22521361
PubMed Central IDPMC3340505
Grant ListHD065286 / HD / NICHD NIH HHS / United States
MH087123 / MH / NIMH NIH HHS / United States
GM061354 / GM / NIGMS NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
/ / Intramural NIH HHS / United States
P01 GM061354 / GM / NIGMS NIH HHS / United States
R21 HD065286 / HD / NICHD NIH HHS / United States
F32 MH087123 / MH / NIMH NIH HHS / United States