|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Talkowski, 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, MJ, Morton, CC, Gusella, JF|
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.