title: De novo gene disruptions in children on the autistic spectrum.
abstract: Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Iossifov
authors.forename: Michael
authors.initials: M
authors.lastname: Ronemus
authors.forename: Dan
authors.initials: D
authors.lastname: Levy
authors.forename: Zihua
authors.initials: Z
authors.lastname: Wang
authors.forename: Inessa
authors.initials: I
authors.lastname: Hakker
authors.forename: Julie
authors.initials: J
authors.lastname: Rosenbaum
authors.forename: Boris
authors.initials: B
authors.lastname: Yamrom
authors.forename: Yoon-Ha
authors.initials: YH
authors.lastname: Lee
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Narzisi
authors.forename: Anthony
authors.initials: A
authors.lastname: Leotta
authors.forename: Jude
authors.initials: J
authors.lastname: Kendall
authors.forename: Ewa
authors.initials: E
authors.lastname: Grabowska
authors.forename: Beicong
authors.initials: B
authors.lastname: Ma
authors.forename: Steven
authors.initials: S
authors.lastname: Marks
authors.forename: Linda
authors.initials: L
authors.lastname: Rodgers
authors.forename: Asya
authors.initials: A
authors.lastname: Stepansky
authors.forename: Jennifer
authors.initials: J
authors.lastname: Troge
authors.forename: Peter
authors.initials: P
authors.lastname: Andrews
authors.forename: Mitchell
authors.initials: M
authors.lastname: Bekritsky
authors.forename: Kith
authors.initials: K
authors.lastname: Pradhan
authors.forename: Elena
authors.initials: E
authors.lastname: Ghiban
authors.forename: Melissa
authors.initials: M
authors.lastname: Kramer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Parla
authors.forename: Ryan
authors.initials: R
authors.lastname: Demeter
authors.forename: Lucinda L
authors.initials: LL
authors.lastname: Fulton
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Magrini
authors.forename: Kenny
authors.initials: K
authors.lastname: Ye
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Darnell
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schatz
authors.forename: W Richard
authors.initials: WR
authors.lastname: McCombie
authors.forename: Michael
authors.initials: M
authors.lastname: Wigler
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000209:etiology / Q000235:genetics*; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D018628:Gene Dosage; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D010290:Parents; D010641:Phenotype
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human