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De novo gene disruptions in children on the autistic spectrum.

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 theĀ 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.

Pubmed ID: 22542183


  • Iossifov I
  • Ronemus M
  • Levy D
  • Wang Z
  • Hakker I
  • Rosenbaum J
  • Yamrom B
  • Lee YH
  • Narzisi G
  • Leotta A
  • Kendall J
  • Grabowska E
  • Ma B
  • Marks S
  • Rodgers L
  • Stepansky A
  • Troge J
  • Andrews P
  • Bekritsky M
  • Pradhan K
  • Ghiban E
  • Kramer M
  • Parla J
  • Demeter R
  • Fulton LL
  • Fulton RS
  • Magrini VJ
  • Ye K
  • Darnell JC
  • Darnell RB
  • Mardis ER
  • Wilson RK
  • Schatz MC
  • McCombie WR
  • Wigler M



Publication Data

April 26, 2012

Associated Grants

  • Agency: NIMH NIH HHS, Id: 5RC2MH090028-02
  • Agency: NIMH NIH HHS, Id: RC2 MH090028

Mesh Terms

  • Child
  • Child Development Disorders, Pervasive
  • Child, Preschool
  • Family Health
  • Female
  • Fragile X Mental Retardation Protein
  • Gene Dosage
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Models, Molecular
  • Mutation
  • Parents
  • Phenotype