Scientific Publications

Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries.

Publication TypeJournal Article
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 JH, Ha K., Kim HG, Solomon BD, Gropman AL, Lucente D., Sims K., Ohsumi TK, Borowsky ML, Loranger S., Quade B., Lage K., Miles J., Wu BL, Shen Y., Neale B., Shaffer LG, Daly M. J., Morton CC, and Gusella JF
AbstractBalanced 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.
Year of Publication2012
JournalCell
Volume149
Issue3
Pages525-37
Date Published (YYYY/MM/DD)2012/04/27
ISSN Number0092-8674
DOI10.1016/j.cell.2012.03.028
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/22521361?dopt=Abstract