title: Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.
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.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Ian
authors.initials: I
authors.lastname: Blumenthal
authors.forename: Vamsee
authors.initials: V
authors.lastname: Pillalamarri
authors.forename: Colby
authors.initials: C
authors.lastname: Chiang
authors.forename: Adrian
authors.initials: A
authors.lastname: Heilbut
authors.forename: Carl
authors.initials: C
authors.lastname: Ernst
authors.forename: Carrie
authors.initials: C
authors.lastname: Hanscom
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rossin
authors.forename: Amelia M
authors.initials: AM
authors.lastname: Lindgren
authors.forename: Shahrin
authors.initials: S
authors.lastname: Pereira
authors.forename: Douglas
authors.initials: D
authors.lastname: Ruderfer
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirby
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: David J
authors.initials: DJ
authors.lastname: Harris
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Kyungsoo
authors.initials: K
authors.lastname: Ha
authors.forename: Hyung-Goo
authors.initials: HG
authors.lastname: Kim
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Solomon
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Gropman
authors.forename: Diane
authors.initials: D
authors.lastname: Lucente
authors.forename: Katherine
authors.initials: K
authors.lastname: Sims
authors.forename: Toshiro K
authors.initials: TK
authors.lastname: Ohsumi
authors.forename: Mark L
authors.initials: ML
authors.lastname: Borowsky
authors.forename: Stephanie
authors.initials: S
authors.lastname: Loranger
authors.forename: Bradley
authors.initials: B
authors.lastname: Quade
authors.forename: Kasper
authors.initials: K
authors.lastname: Lage
authors.forename: Judith
authors.initials: J
authors.lastname: Miles
authors.forename: Bai-Lin
authors.initials: BL
authors.lastname: Wu
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Neale
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
mesh_terms: D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis / Q000235:genetics*; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D056915:DNA Copy Number Variations; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009420:Nervous System / Q000254:growth & development; D012559:Schizophrenia / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction