Author/Authors :
Michael E. Talkowski، نويسنده , , Jill A. Rosenfeld، نويسنده , , Ian Blumenthal، نويسنده , , Vamsee Pillalamarri، نويسنده , , Colby Chiang، نويسنده , , Adrian Heilbut، نويسنده , , Carl Ernst، نويسنده , , Carrie Hanscom، نويسنده , , Elizabeth Rossin، نويسنده , , Amelia M. Lindgren، نويسنده , , Shahrin Pereira، نويسنده , , Douglas Ruderfer، نويسنده , , Andrew Kirby، نويسنده , , Stephan Ripke، نويسنده , , David J. Harris، نويسنده , , Ji-Hyun Lee، نويسنده , , Kyungsoo Ha، نويسنده , , Hyung-Goo Kim، نويسنده , , Benjamin D. Solomon، نويسنده , , Andrea L. Gropman، نويسنده , , et al.، نويسنده ,
Abstract :
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.
